Nicotine enhances the biosynthesis and secretion of transthyretin from thechoroid plexus in rats: Implications for beta-amyloid formation

Epidemiological studies indicated that cigarette smoking protects against t he development of several neurodegenerative disorders, including Alzheimer' s disease (AD). However, the molecular mechanism(s) underlying this is poor ly understood. To gain insight into these protective effects, we used diffe rential display PCR (DD-PCR) to amplify RNA from various brain regions of r ats self-administering (SA) nicotine compared with yoked-saline controls. W e found that the transthyretin (TTR) gene, whose product has been shown to bind to amyloid beta (A beta) protein and prevent A beta aggregation, was m ore abundantly expressed (similar to 1.5- to 2.0-fold) in the brainstem and hippocampus (areas containing choroid plexus) of nicotine SA rats. Subsequ ently, quantitative reverse transcription-PCR analysis confirmed these DD-P CR findings and demonstrated that nicotine increased TTR mRNA levels in the se regions in a time- and dose-dependent manner. Significantly higher TTR p rotein concentrations were also detected in the ventricular CSF of nicotine -treated rats. In contrast, no differences either in plasma TTR or in CSF a nd plasma retinol-binding protein were detected. Immunohistochemical analys is showed that immunoreactive TTR was 41.5% lower in the choroid plexus of nicotine-treated rats compared with the saline controls. On the basis of th ese data, we speculate that the protective effects of nicotine on the devel opment of AD may be attributable, in part, to the increased biosynthesis an d secretion of TTR from the choroid plexus. These findings also point towar d new approaches that may take advantage of the potentially novel therapeut ic effects of nicotinic agonists in patients with AD.